Bipolar Disorder (BD) is a common, severe, chronic and often life-threatening illness. The discovery of lithium's efficacy as a mood-stabilizing agent has since revolutionized the treatment of patients with BD. Elucidation of the mechanism(s) by which lithium stabilizes an underlying dysregulation of limbic and limbic-associated function also offers the potential to delineate the underlying pathophysiology of BD; however, a major problem inherent in neuropharmacologic research is the difficulty in attributing therapeutic relevance to any observed biochemical finding. One powerful approach is to identify common biochemical targets, which are modified by drugs belonging to the same therapeutic class (e.g. mood-stabilizing agents) but possessing distinct chemical structures when administered in a "therapeutically relevant" paradigm (i.e., effects which are observed upon chronic drug administration, and yet persist beyond abrupt drug discontinuation). In this context, it is noteworthy that both valproic acid (VPA) and lithium, with different chemical structures, belong to the same therapeutic class and cause considerable inhibition of protein kinase C (PKC). The PKC signaling pathway is clearly a target for the actions of two structurally highly dissimilar antimanic agents -- lithium and VPA. Do these effects of lithium and VPA on PKC signaling have any clinical relevance? There is thus a clear need to investigate the potential efficacy of a direct PKC inhibitor in the treatment of acute mania. There is currently only one relatively selective PKC inhibitor available for human use- Tamoxifen. Tamoxifen (TAM), a synthetic nonsteroidal antiestrogen, has been widely used in the treatment of breast cancer. TAMs potent inhibitory effects on PKC are striking. Recently, our group conducted the first open-label study with TAM in acute mania. In this study, TAM resulted in a significant decrease in manic symptoms within a short period of time (3-7 days). The overarching goal of this proposal is to test the hypothesis that PKC inhibition is part of the mechanism of the therapeutic effect of mood stabilizing drugs. The proposal derives from and builds on our published open-label study of TAM in acute mania (Bebchuk et al., 2000). The study has been completed. In this double-blind, placebo-controlled study, 16 subjects with bipolar disorder, manic or mixed, with or without psychotic features were randomly assigned to receive tamoxifen (20-140 mg/day; n=8) or placebo (n=8) for 3 weeks. Subjects on tamoxifen showed significant improvement in mania compared to placebo as early as 5 days, an effect that remained significant throughout the 3 week trial. The effect size for the drug difference was very large (d=1.08, 95% C.I. = 0.45 to 1.71) after 3 weeks (p=.001). At study endpoint, response rates were 63% for tamoxifen and 13% for placebo.[unreadable] [unreadable] The study is now completed. We will now pursue to conduct clinical trials in acute mania with more selective PKC inhibitors. The identification of PKC as a promising target for bipolar disorder is the result of over a decade of work by our group consisting of molecular pharmacology studies, animal studies, human assay studies, and proof-of-concept studies. To our knowledge, PKC is the first mechanistically distinct target identified for the treatment of bipolar disorder.